2,2-di-and 2,2,3-tri-lower alkyl chroman-and chromen-ols and salts,ethers and esters thereof

ABSTRACT

NOVEL CHEMICAL COMPOUND ARE THEIR SALTS, ETHERS AND ESTERS ARE DISCLOSED WHEREIN THE COMPOUNDS HAVE THE FORMULAS:   2,2,3-TRI(R1-),4-(PYRIDIN-4-YL),5-X,7-R2-CHROMAN, 2,2-DI-   (R1-),4-(PYRIDIN-4-YL),5-X,7-R2-2H-CHROMENE, AND 2-(O=),   4-(PYRIDIN-4-YL),5-X,7-R2-2H-CHROMENE   IN WHICH R1 IS LOWER ALKYL HAVING 1 TO 6 CARBON ATOMS, R2 IS ALKYL HAVING 1 TO 20 CARBON ATOMS OR CYCLOALKYLLOWER-ALKYL, THE CYCLOALKYL PART HAVING 3 TO 8 CARBON ATOMS, AND X IS OH OR A PHARMACEUTICALLY ACCEPTABLE SALT INCLUDING AN ALKALI METAL SALT OR ALKALINE EARTH METAL SALT, OR AN ETHERIFIED OR ESTERIFIED OH-GROUP, EXCLUSIVE OF AMINO ACID ESTERS. COMPOUNDS I AND II POSSESS BENEFICIAL PHARMACODYNAMIC ACTIVITY WITH RESPECT TO THE CARDIOVASCULAR AND CENTRAL NERVOUS SYSTEM, AND COMPOUNDS III ARE INTERMEDIATES FOR USE IN THE PREPARATION OF COMPOUNDS I AND II.

United States Patent Office 3,726,883 Patented Apr. 10, 1973 Int. Cl.C0711 31/28 US. Cl. 260-297 B 26 Claims ABSTRACT OF THE DISCLOSURE Novelchemical compounds and their salts, ethers and esters are disclosedwherein the compounds have the formulas:

/N G C] X X X -R1 -R3 R R1 (In (III) in which R, is lower alkyl having 1to 6 carbon atoms,

R; is alkyl having 1 to 20 carbon atoms or cycloalkyllower-alkyl, thecycloalkyl part having 3 to 8 carbon atoms, and

X is OH or a pharmaceutically acceptable salt including an alkali metalsalt or alkaline earth metal salt, or an etherified or esterifiedOH-group, exclusive of amino acid esters.

Compounds I and II possess beneficial pharmacodynamic activity withrespect to the cardiovascular and central nervous system, and compoundsIII are intermediates for use in the preparation of compounds I and II.

CROSS REFERENCE TO RELATED APPLICATIONS This application is acontinuation-in-part of application Ser. No. 36,466 filed May 11, 1970,which is a continuation-in-part of application Ser. No. 1,543, filedJan. 8, 1970, which in turn is a continuation-in-part of applicationSer. No. 866,743 filed Oct. 15, 1969 and which in its turn is acontinuation-in-part of application Ser. No. 630,808 filed Apr. 14,1967, and all now abandoned.

The present invention relates to the new chemical compounds I and II:

X X X I I I l R L R R -R1 0 -RI R1 0/ Rl 0/ 0/ I II III and non-toxicacid addition salts thereof,

wherein R is lower alkyl having 1 to 6 carbon atoms,

R is alkyl having 1 to 20 carbon atoms or cycloalkyllower-alkyl, thecycloalkyl part having 3 to 8 carbon atoms, and

X is OH or a pharmaceutically acceptable salt thereof including analkali metal salt or alkaline earth metal salt, or an etherified oresterified OH-group, exclusive of amino acid esters,

which are useful as antidepressants and anti-anxiety agents and whichare non-toxic when administered orally or parenterally. Compounds IIIare valuable coumarin intermediates for I and II.

Extensive work has been carried out in synthesizing pharmacodynamicallyactive chemical compounds to find non-toxic compounds which will producecertain desired results on the cardiovascular and central nervous systemwithout complete success.

It is, therefore, a major object of this invention to provide novelcompounds I and II which possess pharmacodynamic activity with respectto hypertension and analgesia, and which are useful as antidepressantsand anti-anxiety agents. It is another object to provide compounds ofthe character described which exhibit low toxicity, and which may benondependence-providing drugs. A further object resides in solubilizedderivatives of the S-OH group when X=OH and esters and ethers of theS-OH group which are non-toxic when administered orally or parenterally.

This invention therefore resides in the chemical compounds I and IIwhich are herein designated as 2,2,3-trilower-alkyl-7-alkyl- (and7-cycloalkyl-lower-alkyl-)4-(4- pyridyl)-5-chroman-ols, and2,2-di-lower-alkyl-7-alkyl- (and 7cycloalkyl-lower-alkyl-)4-(4-pyridyl)-2H-chromen-S-ols and their alkaliand alkaline earth metal, acid addition and other pharmaceuticallyacceptable salts, and ether and ester derivatives thereof, excludingamino acid and esters.

Illustrative embodiments of the invention are those of Formulas I andII, respectively:

wherein R R and X have the above stated meanings. Compound II in which R=methyl, R methyloctyl and X=OH or ONa represents a preferred and bestmode exemplification of the invention.

The term lower-alkyl as used to define R means saturated, monovalentaliphatic radicals, including straight and branched-chain radicals offrom one to six carbon atoms, as illustrated by methyl, ethyl, propylisopropyl, butyl, sec.-butyl, amyl and hexyl. Each R is preferablymethyl.

The term alkyl as used to define R means saturated, monovalent aliphaticradicals, including straight and branched-chain radicals of from one totwenty carbon atoms, as illustrated by methyl, ethyl, propyl, nbutyl,n-amyl, n-hexyl, 2-heptyl, n-heptyl, 3-methyl-2- octyl, n-octyl, nonyl,tetradecyl, n-hexadecyl, eicosanyl, and the like, and the termcycloalkyl means cyclic, saturated aliphatic radicals of from three toeight carbon atoms, as illustrated by cyclopropyl, cyclobutyl,Z-methylcyclobutyl, cyclohexyl, 4-methylcyclohexyl, cyclooctyl, and thelike. Preferably R is a methyloctyl group, especially 3-methyl-2-octyl.

X as used herein means preferably OH but includes salts such as --ONa or-OK or other pharmaceutically acceptacle alkali and alkaline earth saltsand esters (other than amino acid esters) and ethers.

When X is an ester group, it is an acyloxy radical having from 1 to 20carbon atoms, preferably an acetoxy, propionoxy, butyroxy, hexanoyloxy,octoyloxy, decanoyloxy or dodecanoyloxy group or an aromatic acyloxygroup such as a benzoyloxy or naphthoyloxy group. However X may also bederived from a polybasic acid such as malonic, succinic, glutamic orcitric acid. The polybasic acid may also be inorganic in nature such asphosphoric, carbonic or carbamic acid. Polybasic acid derivatives may beformed as mono-chromenol esters with the other basic groups of the acidbeing in the free acid or salt form or in the form of other esters,particularly lower-alkyl esters thereof. For example X may represent ahemisuccinate, a mono-phosphate ester of the free acid, alkalimetal saltor dior tri-ester forms, or may be a loweralkyl carbonate or carbamateester group.

When X is an ether group this may be a simple alkyl ether, particularlya lower-alkyl ether, so that X may represent a methoxy, ethoxy, propoxyor butyroxy group. However the alkyl group may be substituted by halogenatom(s) or amino group(s) and preferred ethers for present use are theethers of N,N-di-(lower-alkyl)-2- arninoethanol. Also in the case oftertiary amino groups, the groups attached to the nitrogen atom may belinked to each other or through further hetero atoms to formheterocyclic groups including the nitrogen of the amino group to whichthey are both attached. When basic groups are present in the ethermoiety, these may be in the form of salts of appropriate acids.

-It will thus be appreciated that Formulas I and II not only representthe structural configuration of the compounds of the invention as shown,but are also representative of the respective structural entities commonto all of the compounds of Formulas I and II whether in the formsillustrated or in the forms of their acid salts or other derivatives.They also include geometric and optical and stereo isomers. It has beenfound that by virtue of this common structural entity, these compoundsand their acid addition salts or other derivatives have pharmacodynamicactivity of a type to be more fully described hereinbelow. Thispharmacodynamic activity is utilized in useful form for pharmaceuticalpurposes by employing the compounds themselves or the acid additionsalts or other derivatives formed from pharmaceutically-acceptable acidsor esters of strong acids, that is, acids or esters whose anions areinnocuous to the animal organism in effective doses of the salts so thatbeneficial properties existing in the common structural 4 entityrepresented by the free bases are not vitiated by side-effectsascribable to the anions.

In utilizing this pharmacodynamic activity of the salts of theinvention, pharmaceutically-acceptable non-toxic salts are used.Although enhanced water-insolubility, increased toxicity, or lack ofcrystalline character may make some particular salt species lesssuitable or less desirable for use as such in a given pharmaceuticalapplication, the water-insoluble or more toxic salts can be converted topharmaceutically-acceptable compounds by techniques well known in thepharmaceutical art.

It will be appreciated from the foregoing that all of the acid additionsalts of our new compounds are useful and valuable compounds regardlessof considerations of solubility, toxicity, physical form, and the like,and accordingly are within the purview of the instant invention.

The invention further resides in the. chemical compounds (III) which areherein designated as 5-X-7-alkyl- (and7-cycloalkyl-lower-alkyl-)-4-(4-pyridyl) coumarins having the formula:

III

wherein R and X have the meanings given above, and which are useful asintermediates in the preparation of the compounds of Formulas I and II.

Compounds of Formula I (X=OH) may be prepared by reacting a5-hydroxy-7-alkyl-(and 7-cycloalkyl-loweralkyl-)4-(4-pyridyl) coumarin,illustrated above by Formula III (X=OH) with a lower alkyl magnesiumhalide to produce a 2,2,3-tri-lower-alkyl-7-alkyl-(and 7-cycloalkyl-lower-alkyl-)4-(4-pyridyl) 5 chromanol of Formula I (X=OH).The reaction is carried out in an organic solvent which is inert underthe conditions of the reaction. Suitable solvents are diethyl ether,dibutyl ether, tetrahydrofuran, anisole, pyridine, and the like. It ispreferred to add a solution of the 5-hydroxy-7-alkyl- (and7-cycloalkyl-lower-alkyl-)4-(4-pyridyl) coumarin in anisole solution toa solution of the Grignard reagent in anisole. The reaction is carriedout at an elevated temperature, preferably at C. for an extended periodof time, e.g., at least 24 hours.

Compounds of Formula II (X=OH) may be prepared by reacting a5-hydroxy-7-alkyl-(and 7-cycloalkyl-loweralkyl-)4-(4-pyridyl) coumarin,illustrated above by Formula III (X=OH), with a lower alkyl magnesiumhalide to produce a 2,2-di-lower-alky1-7-alkyl-(and 7-cycloa1kyl-lower-alkyl-) 4- (4-pyridyl -2H-chromen-5-ol of Formula II(X=OH). The reaction is carried out in an organic solvent as describedabove and in the same manner except that the reaction temperature ismaintained at a lower level.

The preparation of the coumarin intermediates of Formula III (X=OH) maybe carried out, for example, by reactingmethyl-,S-oxo-4-pyridine-propionate with a 5- alkyl-(and5-cycloalkyl-lower-alkyl-)resorcinol to produce a 5-hydroXy-7-alkyl-(and7-cycloalkyl-lower--alkyl-) 4-(4-pyridyl) coumarin of Formula III(X=OH). The reaction is carried out in a mixture of concentratedsulfuric acid and phosphorus oxychloride, or in the presence of othercondensation agents such as aluminum chloride,

hydrogen chloride, and polyphosphoric acid, and is illustrated by theequation:

P 0013 -R2 H:

wherein R is as defined above.

The resulting -hydroxy-7-alkyl-(and7-cycloalkyllower-alkyl)4-(4-pyridyl) coumarins are preferably isolatedby the addition of a base to the reaction mixture to convert the salt tothe free base.

Instead of methyl-fi-oxo-4-pyridine-propionate, there can be used thecorresponding ethyl or other lower alkyl compound of 1 to 6 carbonatoms.

The intermediate methyl-fi-oxo-4-pyridine-propionate of Formula IV isconveniently prepared according to the procedure of Moifat described inJ. Med. Chem. 7, 449 (1964), and the intermediate S-alkyl-(and5-cycloal-kyllower-alkyl)resorcinols of Formula V are convenientlyprepared according to procedure of Adams, Mackenzi and Loewe describedin J. Am. Chem. Soc., 70, 669 (1948).

Thus, compounds in which X is an esterified derivative, i.e., an acyloxygroup (exclusive of amino acid esters which form no part of thisinvention), are prepared by the reaction of the said chromenols, or areactive derivative thereof such as a metal salt with an esterifyingacid or a reactive derivative thereof such as an acid halide oranhydride. The acid may be monoor poly-basic and organic or inorganic.Examples include acetic acid, succinic acid, phosphoric acid, carbonicacid and carbamic acid.

Compounds in which X is an etherified derivative of the hydroxyl group,including simple ethers broadly, are prepared by the reaction ofreactive derivatives of the etherifying group with a compound in which Xis OH or a reactive derivative thereof such as a metal salt. Thus, forexample, an alkyl halide may be reacted with a compound in which X isONa to produce, an alkyl ether.

The basic groups such as amino groups may be in the form of salts withacids.

The derivatives of the hydroxyl group may be chonsen to modify thephysical or chemical properties of the compound. Thus, for example,while many compounds in which X is OH are found to be sparingly solublein aqueous media or virtually insoluble, a compound of the formula:

I /Et I O CH2CH2N Et CH3 q CH-CH-CsHu 0 CH3 H3 H3 was found to be freelysoluble in dilute hydrochloric acid and the hydrochloric acid salt wassoluble in water.

The derivatives are selected or chosen to have acceptable pharmaceuticalproperties, especially low toxicity.

Preparation of the derivatives of the OH group is conveniently performedusing the chroman or chromen derivatives of Formulas I and II but insome cases the OH derivative may be formed at an earlier stage in thepreparation, for example, using the coumarin of Formula III. Clearly thenature of the derivative will determine Whether it will survive thelater stages of the prepara- 6 tion. Thus, for example, etheri-fiedderivatives will often be stable while esterified derivatives may behydrolyzed back to the OH group.

In the preparation of some derivatives modified procedure may be foundpreferable. For example, in the preparation of phosphate derivatives ofcompounds in which X is OH, a reaction scheme as outlined below may beemployed:

(T)/OCHzCaH5 fi C1P\ OOHzChH;

O OCHtCaHr O OH 0 ON, T Hz/catalyst T NaOH T i i OCHzCuHz, OH I ON,

The compounds of Formulas I and II have been shown to possess centralnervous system activity as evidenced by gross overt changes induced byparenteral and oral administration in mice and rats in standard testsinvolving observations of psychomotor activity, reactivity to stimuli,and ability to perform normal, non-conditioned motor tasks. Thecompounds also show activity in a number of conditioned behavioral testsin monkeys. This activity indicates their usefulness as psychotropicagents. In addition, certain of the compounds produce depressor responsein cat blood pressure studies.

The compounds can be prepared for use by dissolving under sterileconditions a salt form of the compounds in water (or an equivalentamount of a non-toxic acid if the compounds of Formulas I and II areused), or in a physiologically compatible aqueous medium such as saline,and stored in ampoules for intramuscular injection. Alternatively, theycan be incorporated in unit dosage form as tablets or capsules for oraladministration either alone or in combination with suitable adjuvants orexcipients such as calcium carbonate, starch, lactose, talc, magnesiumstearate, gum acacia, and the like. Still further the compounds can beformulated for oral administration in aqueous alcohol, glycol or oilsolutions or oil-water emulsions in the same manner as conventionalmedicinal substances are prepared.

The molecular structures of the compounds of our invention were assignedon the basis of a study of their infrared, ultraviolet and NMR spectra,of mass spectrometry and their transformation products; and they wereconfirmed by the correspondence of calculated and found values for theelementary analyses for representative examples.

The invention is illustrated by the following representative examples.

EXAMPLE 1 5-hydroxy-7-(3-methyl-2-octyl)-4-(4-pyridyl) coumarin To amixture of 2.1 g. (0.0117 mole) of methyl-B-oxo- 4-pyridine-propionateand 2.8 g. (0.0118 mole) of 5-(3- methyl-Z-octyl) resorcinol was addeddropwise with cooling 5 ml. of concentrated sulfuric acid. The mixturewas then treated all at once with 3 ml. of phosphorus oxychlorride andthe viscous solution was stirred at room temperature for 48 hours. Itwas then poured into cold potassium bicarbonate solution and extractedwith ether several times. The combined ether extract was washed, driedand evaporated to leave a yellow solid which was recrystallized fromdilute ethanol to give 3.4 g. of 5- hydroxy-7-(3-methyl2-octyl) 4 (4pyridyl) coumarin. The compound had a melting point of 191-194 C. andshowed an ultraviolet absorption at 315 [Ii 1..

Analyis.-Calculated for C H O -N (percent): C,

75.59; H, 7.45; N, 3.83. Found (percent): C, 75.42; H, 7.43; N, 3.76.

7 EXAMPLE 2 2,2,3-trimethyl-7- (3 -methyl-2-octyl) -4- (4-pyridyl-chromanol Methyl bromide was bubbled into a stirred mixture of.

18.0 g. (0.75 mole) of magnesium and dry ether under nitrogen until allthe magnesium had dissolved. The ether was then distilled andsimultaneously replaced with dry anisole maintaining constant volume.After all the ether had been removed, 27.6 g. (0.075 mole) of the 5-hydroxy-7- 3-methyl-2-octyl -4- 4-pyn'dyl) coumarin of Example 1 inanisole solution was added dropwise. When addition was complete themixture was stirred and heated at 100 C. for 2 days. The mixture waspoured into a large excess of 4 N sulfuric acid and steam-distilled toremove anisole. The residue was extracted with ether, washed, dried andevaporated to leave a reddish oil. This was dissolved in 250 ml. ofheptane, 5 ml. of 48% hydrobromic acid was added, and the mixture wasthen refiuxed for -6 hours. After cooling the heptane was removed on arotary evaporator and the residue was ex tracted with ether. Theethereal extract was washed with sodium bicarbonate solution, then withwater and dried over sodium sulfate. On evaporation of the ether, agummy residue was obtained which crystallized on trituration Wtihacetonitrile to give 6.0 g. of 2,2,3-trimethyl-7-(3-methyl-2-octyl)-4-(4-pyridy1)-5-chromanol of M.P. 192-l95 C.

Analysis-Calculated for C H O N (percent): C, 78.94; H, 9.43; N, 3.54.Found (percent): C, 78.80; H, 9.38; N, 3.47.

EXAMPLE 3 2,2-dimethyl-7-( 3-methyl-2-octyl -4- (4-pyridyl-2H-chromen-5-ol A solution of 5.0 g. (0.0137 mole) of the S-hydroxy-7-(3-methyl-2-octyl)-4-(4-pyridyl) coumarin of Example 1 in anisole wasadded dropwise to a solution of methyl magnesium bromide (prepared from3.3 g. (0.138 mole) of magnesium as described in the previous example)in anisole. When the addition was complete the mixture was stirred andheated at 50 C. for 16 hours. After working up in a similar manner asdescribed in Example 2, a solid was obtained which was recrystallizedfrom acetonitrile to give 2.9 g. of 2,2-dimethyl-7-(3-methyl-2-octyl)-4-(4-pyridyl)-2H-chromen-5-ol of M.P. 85-90 C. It showed ultravioletabsorption at 263 mp.

AELOH max.

AnaZysis.Calculated for C H O N (percent): C, 78.94; H, 9.43; N, 3.54.Found (percent): C, 78.80; H, 9.38; N, 3.47.

EXAMPLE 4 5-hydroxy-7-methyl-4-(4-pyridyl) coumarin To a mixture of 5.4g. of methyl-B-oxo-4-py'ridinepropionate and 3.75 g. of resorcinol wasadded dropwise with cooling, 15 ml. of concentrated sulfuric acid. Themixture was then treated all at once with 6 ml. of phosphorusoxychloride and the viscous solution was stirred at room temperature for16 hrs. and then poured into ammonium hydroxide solution containing iceand the pH adjusted to neutral with potassium bicarbonate solution. Afine precipitate was obtained which was filtered, and recrystallizedfrom boiling ethanol to give 6.5 g. of 5- hydroxy-7-methyl-4-(4-pyridyl)coumarin of M.P. 304- 306 C.

Analysis.-Calculated for C H NO /2H O (percent): C, 68.7; H, 4.58; N,5.35. Found (percent): C, 68.82; H, 4.63; N, 5.42. It showed ultravioletabsorption at 314 m The structure was confirmed by NMR analysis to be:

EXAMPLE 5 2,2,7-trimethyl-4-(4-pyridyl)-2H-chromen-5-ol A suspension of2 g. of 5-hydroxy-7-methyl-4- 4- pyridyl) coumarin in anisole was addedin small portions to a solution of methyl mangesiurn bromide (preparedfrom 1.9 g. of magnesium as described in Example 2) in anisole. When theaddition was complete, the mixture was stirred and heated at 50 C. for16 hrs. After workup in a similar manner as described in Example 2, asolid was obtained which was recrystallized from methanol/acetonitrilemixture to give 0.7 g. of 2,2,7-trimethyl- 4-(4-pyridyl)-2H-chromen-5-olof M.P. 240245 C.

Analysis.--Calculated for C17H17O2N (percent): C, 76.38; H, 6.41; N,5.24. Found (percent): C, 76.20; H, 6.31; N, 5.42.

The structure was confirmed by NMR analysis to be:

I OH

HsC

EXAMPLE 6 7-n-heptyl-5-hydroxy-4-(4-pyridyl) coumarin N 317 mp.

max.

Analysis.-Calculated for C H N0 (percent): C, 74.75; H, 6.9; N, 4.15.Found (percent): C, 75.0; H, 7.1; N, 4.3.

EXAMPLE 7 2,2-dimethyl-7-n-heptyl-4- (4-pyridyl)-2H-chromen-5-ol Asolution of 7-n-heptyl-S-hydroxy-4-(4-pyridyl) coumarin (20.22 g., 0.06mole) in dry benzene (400 ml.) was added dropwise to a solution ofmethyl magnesium bromide (prepared from magnesium (14.58 g., 0.6 g.atom) and methyl bromide in ether (400 ml.)). When addition wascomplete, the mixture was refluxed for 2 hours, cooled, and poured intosaturated ammonium chloride solution (2 1.) with stirring. The organiclayer was separated, washed, dried and evaporated to give a brown oilwhich solidified (18.1 g., M.P.-60 C.). This material was refluxed inglacial acetic acid for 2 hours, and then the solution was poured intowater (1.l.) with stirring. The solid which separated was extracted intoether and the extract washed with sodium bicarbonate solution and water.After drying, removal of the solvent gave a brown gum which, oncrystallization from aqueous acetonitrile (charcoal) gave2,2-dimethy1-7-n-heptyl-4-(4-pyridy1)- 2H-chromen-5-ol (6.76 g., 32%),M.P. 154-155 0.,

Analysis-Calculated for C H NO /2H O (percent) C, 76.7; H, 8.3; N, 3.9.'Found (percent): C, 76.6; H,

EXAMPLE 8 5-hydroxy-7-n-pentyl-4-(4-pyridyl) coumarin To a mixture ofethyl isonicotinoylacetate (26.8 g., 0.139 mole) andS-n-pentylresorcinol (25 g., 0.139 mole) was added concentrated sulfuricacid (60 ml.) and phosphorus oxychloride (36 ml.) at -5" C. Afterstirring for 20 hours at room temperature, working up as in Example 4gave -hydroxy-7-n-pentyl-4 (4-pyridyl) coumarin (32.0 g., 72% M.P.182-184 C. as yellow crystals ex aqueous ethanol.

A212? 317 my Analysis.--Calculated for C H NO' (percent): C, 73.8; H,6.15; N, 4.5. Found (percent): C, 73.6; H, 6.3; N, 4.4.

EXAMPLE 9 2,2-dimethyl-7-n-pentyl-4- (4-pyridyl) -2H-chromen-5-ol Asolution of 5-hydroxy-7-n-pentyl-4-(4-pyridyl) coumarin (5.0 g., 0.016mole) in dry benzene (100 ml.) was added dropwise to a solution ofmethyl magnesium bromide [from magnesium (3.84 g., 0.16 g. atom) andmethyl bromide in ether (100 ml.)]. Following the procedure outlined inExample 7, there was obtained 2,2-dimethyl-7-n-pentyl-4-(4-pyridyl)-2H-chromen-5-ol (2.01 g., 39%), M.P.173174 C. ex acetonitrile-methanol charcoal).

Analysis.-Calculated for C H NO (percent): C, 78.0; H, 7.7; N, 4.3.Found (percent): C, 78.0; H, 8.0; N, 4.3.

EXAMPLE 10 2,2,3-trimethyl-7-n-pentyl-4-( 4-pyridyl)-chroman-5 -o15-hydroxy-7-n-pentyl-4- (4-pyridyl) coumarin (21.7 g. 0.07 mole) in dryanisole (100 ml.) was added dropwise over 30 minutes to methyl magnesiumbromide in anisole (150 ml.) prepared as described in Example 2 frommagnesium (16.8 g., 0.7 g. atom) and methyl bromide in ether (300 ml.),followed by displacement of ether. After heating at 100 C. for 48 hours,the mixture was poured into excess 4 N sulfuric acid and steam distilledto remove the anisole. The residue was extracted into ether, washed,dried and evaporated to give an oil which was then refluxed in glacialacetic acid for 3 hours. After pouring into water, extraction withether, and washing with sodium bicarbonate solution, an oil (11.8 g.)was obtained from which a solid (4.3 g.) M.P. 202-204 C. was obtained bysublimation at 200 C./ 0.2 mm. Two crystallizations from acetonitrileafforded 2,2,3-trimethyl- 7-n-pentyl-4-(4pyridyl)-chroman-5-ol (2.8 g.,11.5%), M.P. 210-211 C.

Analysis.-Calculated for C H NO (percent): C, 77.8; H, 8.6; N, 4.1.Found (percent): C, 78.05; H, 8.9; N, 3.9.

EXAM PDE 11 5-hydroxy-7-n-nonyl-4-(4-pyridyl) coumarin To a mixture ofethyl isonicotinoylacetate (9.6 g., 0.05 mole) and 5-n-nonylresorcinol(11.8 g., 0.05 mole) was added concentrated sulfuric acid (30 ml.) andphosphoryl chloride (20 ml.) at 0-5 C. The mixture was stirred 10 for 17hours at room temperature and worked up as in Example 4 to give5-hydroxy-7-n-nonyl-4-(4-pyridyl) coumarin (9.2 g., 51%), M.P. 154-155C. ex aqueous ethanol.

Analysis.-Calculated for C23H27NO3 (percent): C, 75.6; H, 7.45; N, 3.8.Found (percent): C, 75.7; H, 7.7; N, 3.8.

EXAMPLE 12 2,2-dimethyl-7-n-nonyl-4- (4-pyridyl) -2H-chromen-5-ol Asolution of 5 hydroxy 7-n-nonyl-4-(4-pyridyl) coumarin (18.25' g., 0.05mole) in dry benzene (300 ml.) was added dropwise to a stirred solutionof methyl magnesium bromide (0.5 mole) in dry other ml.). Following theprocedure outlined in Example 7 there was obtained2,2-dimethyl-7-n-nonyl-4-(4-pyridyl)-2H- chromen-S-ol (8.32 g., 44%),M.P. 148149 C. (acetonitrile).

Analysis-Calculated for C H NO (percent) C, 79.1; H, 8.8; N, 3.7. Found(percent): C, 79.0; H, 8.7; N, 3.5.

EXAMPLE 13 5-hydroxy-7-(2-octyl)-4-(4-pyridyl) coumarin To a mixture ofethyl isonicoti-noylacetate (25.1 g., 0.13 mole) and5-(2-octyl)resorcinol (29.0 g., 0.13 mole) was added concentratedsulfuric acid (60 ml.) and phosphoryl chloride (36 ml.) at 05 C. Themixture was stirred for 17 hours at room temperature and worked up as inExample 4 to give 5-hydroxy-7-(2-octyl)-4-(4- pyridyl) coumarin (37.92g., 82%) M.P. 203205 C. ex aqueous ethanol.

Analysis.-Calculatecl for C H NO (percent): C, 75.2; H, 7.2; N, 39.'Found (percent): C, 75.1; H, 7.3; N, 3.9.

EXAMPLE 14 2,2-dimethyl-7-(2-octyl)-4-(4-pyridyl)-2H-chromen-5-ol Asolution of 5-hydroxy-7-(2-octyl)-4'(4-pyridyl) coumarin (10.1 g., 0.03mole) in dry benzene (100 ml.) was added dropwise to a stirred solutionof methyl magnesium bromide (0.3 mole) in dry ether (150 ml.). Followingthe procedure outlined in Example 7 there was obtained 2,2 dimethyl7-(2-octyl)-4-(4-pyridyl)-2H- chromen-S-ol (3.8 g., 36%), M.P. 152154 C.ex acetonitrile.

Analysis.-Calculated for C H NO (percent): C, 78.9; H, 8.55; N, 3.8.Found (percent): C, 78.5; H, 8.6; N, 3.7.

EXAMPLE 15 5-hydroxy-7- (3-nonyl) -4- (4-pyridyl) coumarin To a mixtureof ethyl isonicotinoylacetate (24.7 g., 0.127 mole) and5-(3-nonyl)-resorcinol (30.0 g., 0.127 mole) was added concentratedsulfuric acid (60 ml.) and phosphoryl chloride (36 ml.) at 05 C. Themixture was stirred for 18 hours at room temperature and worked up as inExample 4 to give 5-hydroxy-7-(3-nonyl)-4-(4- pyridyl) coumarin (31.0g., 67%), M.P. 219221 C. ex aqueous ethanol.

Analysis.-Calculated for C H NO (percent): C, 75.6; H, 7.4; N, 3.8.Found (percent): C, 75.5; H, 7.6; N, 3.8.

EXAMPLE l6 2,2-dimethyl-7-(3- nonyl) -4-(4-pyridyl)-2H- chromen-S-ol Asolution of 5-hydroxy-7-(3-nonyl)-4-(4-pyridyl) coumarin (18.35 g., 0.05mole) in dry benzene (150 ml.) was added dropwise to a stirred solutionof methyl magnesium bromide (0.5 mole) in dry other (200 ml.). Followingthe procedure outlined in Example 7 there was obtained 2,2 dimethyl7-(3-nonyl)-4-(4-pyridyl)-2H- chromen-S-ol (8.25 g., 33.5%) isolated asthe hemihydrate, M.P. 141-142" C. ex acetonitrile.

Analysis.Calculated for C H NO V2 H O (percent): C, 77.3; H, 8.8; N,3.6. Found (percent): C, 77.5; H, 8.8; N, 3.5.

EXAMPLE 17 2,2-diethyl-7-n-heptyl-4-(4-pyridyl)-2H-chromen-5-ol 7n-heptyl-5-hydroxy-4-(4-pyridyl) coumarin (described in Example 6) (6.75g., 0.02 mole) was added portionwise to a stirred solution of ethylmagnesium bromile (0.06 mole) in dry ether (120 ml.). The mixture wasstirred at room temperature for 1 hour and then decomposed by pouringinto a solution of ammonium chloride. The organic layer was separated,dried (MgSO and evaporated to give a yellow solid which oncrystallization from carbon tetrachloride gave the intermediate triol(1.75 g.) M.P. 161-162 C. This intermediate was heated under reflux inglacial acetic acid for 1 hour, cooled and poured into water to give2,2-diethyl-7-n-heptyl-4-(4- pyridyU-ZH-chromen-S-ol (0.9 g., 12%)isolated as the hemihydrate, M.P. 121122 C. (acetonitrile).

Analysis.Calculated for C H NO /2 H O (percent): C, 77.3; H, 8.8; N,3.6. Found (percent): C, 76.9; H, 8.6; N, 3.6.

EXAMPLE 18 2,2-dimethyl-7-n-heptadecyl-4- (4-pyridyl) ZH-chromen-S-olMethyl iodide (28.4 g., 0.2 mole) in dry ether (15 ml.) was addeddropwise to a stirred suspension of magnesium turnings (4.6 g., 0.2mole) in dry ether (125 ml.) under a stream of nitrogen. When all themagnesium had reacted the 7 n-heptadecyl 5 hydroxy-4-(4-pyridyl)coumarin (9.54 g., 0.02 mole) was added without solvent over /2 hour.When the addition was complete the mixture Was stirred at roomtemperature for 1 hr.

The mixture was poured into a saturated solution of ammonium chlorideand extracted with ether. The extract was washed with water, dried (MgSOand evaporated. The residue (8.45 g.) was dissolved in glacial aceticacid (50 ml.) and heated under reflux for 1 hr. After cooling, the darkliquid was poured with stirring into sodium carbonate solution and theprecipitate collected and crystallized from methanol to give2,2-dimethyl-7- n-heptadecyl-4-(4-pyridyl)-2H-chromen-5 01 (4.88 g.,50%), M.P. 120-121 C.

Analysis.-Calculated for C H NO (percent): C, 80.65; H, 10.0; N, 2.85.Found (percent): C, 80.5; H, 10.0; N, 2.7.

The intermediate 7-n-heptadecyl-5-hydroxy-4-(4 pyridyl) coumarin wasprepared by adding concentrated sulphuric acid (30 ml.) and phosphorylchloride (18 ml.) at -5 C. to a mixture of ethyl isonicotinoylacetate(9.7 g., 0.05 mole) and -n-heptadecyl-resorcinol (17.4 g., 0.05 mole)and stirring the mixture for 17 hours at room temperature and thenworking it up as in Example 4 to obtain the7-n-heptadecyl-5-hydroxy-4-(4-pyridyl) coumarin (11.9 g., 50% yield) ofM.P. 117-l18 C. (ethanol).

AnaIysis.-Calculated for C H NO (percent): C, 78.0; H, 9.0; N, 2.9.Found (percent): C, 77.7; H, 911; N, 3.0.

EXAMPLE 19 5-acetoxy-2,2-dimethyl-7-(2-octyl)- 4-(4-pyridyl)-2H-chromen2,2-dimethyl-7-(2-octyl)-4-(4 pyridyl)-2 H-chromen-5- 01 (10.95 g., 0.03mole), anhydrous sodium acetate (3.0 g.) and acetic anhydride (60 ml.)were heated together under reflux for 2 hours. After cooling, themixture was stirred with water (200 ml.) and extracted with ether. Theethereal extract was washed with sodium carbonate solution, washed withwater, dried and evaporated to yield a pale brown oil. Distillation ofthis material gave the acetate (10.0 g., 82%) M.P. 2.06208/0.8 mm.

12 Analysis.Calculated for C H NO (percent): C, 76.7; H, 8.1; N, 3.4.Found (percent): C, 76.8; H, 8.3; N, 3.4.

EXAMPLE 20 The hemisuccinate of 2,2-dimethyl-7-n-pentyl-4-(4-pyridyl)-2H-chromen-5-o1 2,2-dimethyl7-n-pentyl-4-(4pyridyl)-2H-chromen-5- 01 (0.323 g., 0.001 mole) and succinic anhydride(0.1 g., .001 mole) were treated together in a sealed tube at C. for 8hours. After cooling, the glassy product was triturated with ether andthe insoluble material collected by filtration. Crystallization fromethanol gave the hemisuccinate (0.11 g., 26%) M.P. 161-162" C.

Analysis.Calculated for C H NO (percent): C, 70.9; H, 6.9; N, 3.3. Found(percent): C, 71.0; H, 6.9; N, 3.3.

EXAMPLE 21 Diethylaminoethyl ether of 2,2-dimethyl-7-n-pentyl- 4-(4-pyridyl)-2H-chromen-5-ol 2,2-dimethyl-7-n-pentyl-4-(4pyridyl)-2H-chromen-5- 01 (3.23 g., 0.01 mole) in absolute ethanol (5ml.) was treated with a solution of sodium (0.23 g., 0.01 g. atom) inabsolute ethanol (5 ml.). The ethanol was removed in vacuo to yield thesodium salt of the chromen-S-ol. The salt was suspended on dry benzene(10 ml.) and stirred during the dropwise addition of diethylaminoethylchloride (2.71 g., 0.02 mole). When the addition was complete themixture was refluxed for 2 hrs., cooled and extracted with water toremove sodium chloride. After drying (MgSO the benzene was removed invacuo to yield the crude basic ether as a viscous oil.

Treatment of a solution of the crude material in dry other with etherealhydrogen chloride gave the diethyl aminoethyl ether as thedihydrochloride (2.85 g., 58%) which crystallized from acetone-ethanolmixture as the monohydrate of M.P. 182-183 C.

Analysis.-Calculated for C H Cl N O (percent): C, 63.2; H, 8.2; C1,13.85; N, 5.5. Found (percent): C, 63.4; H, 8.1; Cl, 13.5; N, 5.2.

EXAMPLE 22 Diethylaminoethyl ether of 2,2-dimethyl-7-(3-methyl-2-octy1)-4-(4-pyridyl)-2H-chromen-5-ol Using the method described underExample 21 there was prepared the diethylaminoethyl etherdihydrochloride (35%) which crystallized from acetone-ethanol mixture asthe monohydrate of M.P. 182l84 C.

Analysis.-Calculated for C H Cl N O (percent): C, 65.4; H, 8.8; Cl,12.5; N, 4.8. Found (percent): C, 65.8; H, 8.6; Cl, 12.2; N, 4.9.

EXAMPLE 23 Diethylaminoethyl ether of 2,2-dimethyl-7-(2-octyl)-4-(4-pyridyl)-2H-chrornen-5-ol Using the method described under Example21 there was prepared the diethylaminoethyl ether dihydrochloride (65%)which crystallized from acetone-ethanol mixture as the monohydrate ofM.P. 186187 C.

Analysis.Calculated for C H CI N O (percent): C, 64.9; H, 8.6; Cl, 12.8;N, 5.0. Found (percent): C, 64.4; H, 8.8; Cl, 13.0; N, 5.3.

The compounds of Examples 21, 22 and 23 were all highly soluble inwater.

EXAMPLE 24 Methyl ether of 2,2-dimethyl-7-(3-Inethyl-2-qcty1)--pyridyl)-2H-chromen-5-ol Using the method described under Example 21and starting from2,2-dimethyl-7-(3-methyl-2-octyl)-4-(4-pyridyl)-2H-chromen-5-ol andmethyl iodide, this methyl ether was prepared and its structure verifiedby N.M.R. spectroscopy.

13 EXAMPLE 2s Carbamate ester of 2,2-dimethyl-7-(3-methyl- 2-octyl) 4-(4-pyridyl) 2H-chromen-5-ol Trifiuoroacetic acid (1.71 g., 0.015 mole)was added dropwise to a stirred mixture of 2,2-dimethyl-7-(3-methyl-2-octyl)-4-(4-pyridyl)-2H-chromen-5-ol (1.90 g., 0.005 mole) and sodiumcyanate (0.65 g., 0.01 mole) in benzene (15 ml.). After 24 hours,additional sodium cyanate (0.65 g., 0.01 mole) and trifluoroacetic acid(1.14 g., 0.01 mole) were added. After a further three days, water wasadded and the organic layer separated, washed with sodium carbonatesolution and dried over magnesium sulphate. Removal of solvent underreduced pressure gave an oil which crystallized on trituration withether. Recrystallization from ethyl acetate-light petroleum afforded thecarbamate (300 mg., 14%), MP. 170-173" C.

Analysis-Calculated for C H N O (percent): C, 73.9; H, 8.1; N, 6.6.Found (percent): C, 73.6; H, 8.1; N, 6.4.

EXAMPLE 26 Ethyl carbonate ester of 2,2-dimethyl-7-(3-methyl- 2-octyl)4-(4-pyridyl 2H-chromen-5-ol A mixture of2,2-dimethyl-7-(3-methyl-2-octyl)-4- (4- pyridyl)-2H-chromen-5-ol (3.79g., 0.01 mole), ethyl chloroformate (2.17 g., 0.02 mole) anddiethylaniline (2.98 g., 0.02 mole) in dry benzene (60 ml.) was heatedunder reflux with stirring for 4 hours. The solution was cooled, washedsuccessively with hydrochloric acid (5 N), saturated sodium hydrogencarbonate solution and water and dried over magnesium sulphate.Evaporation of solvent under reduced pressure gave the ethyl carbonate(3.40 g., 71%), as a pale yellow gum, the structure of which wasverified by N.M.R. spectroscopy.

In analogous manner, compounds can be made in which the 7-cycloalkylpart of 7-cycloalkyl-lower-alkyl is cyclopropyl, cyclobutyl, cyclohexyland cyclooctyl by substituting the appropriate chromenols for those setforth above. In this way, from such coumarins there are obtainedcompounds such as 2,2-dimethyl-7-methylorethyl-cyclohexyl-4-(4spyridyl)-2H-chromen-5-ol and the7-methyl-cyclopropyl, methyl-cyclobutyl, methylor -ethyl-cycloheptyl andmethyl-cyclooctyl analogs thereof as well as other alkylcycloalkyl orcycloalkylalkyl derivatives.

Compounds of the invention wherein, for example, X is ONa or --OKinstead of OH are prepared in essentially the same manner as compounds(I) and (II) above but by converting the -OH group to alkali metal saltform with a solution of NaOH or KOH, respectively. This is preferablyand most simply carried out on a compound (H). For example, compound(II), wherein the substituents R are both methyl and the substituent Ris methyloctyl, has been converted into the sodium salt in which X isONa. The 2,2-dimethyl-5-hydroxy-7methyloctyl compound is reacted withsodium methoxide, refiuxed for 1 hour and then evaporated to dryness,the product being a yellowish powder having a melting point of 171 to176 C. and being non-crystalline. The sodium salt is soluble in ether,but is only extremely slightly soluble in water and for all practicalpurposes is water insoluble. The sodium salt can be made also by usingsodium hydride or sodium hydroxide in place of sodium methoxide. Thethus produced sodium salt has the formula:

Due to the ionic nature of the nitrogen in the pyridine ring of FormulasI and II, it is possible to form acid addition salts such as those ofHCl, BHr, HI and picric acid [(NO C H OH]. The compounds of Formulas Iand II may be converted to the acid addition salt form by dissolving thecompound in an aqueous solution containing the appropriate acid andisolating the salt by evaporating the solution.

What is claimed is:

1. A member of the group consisting of a compound having the formula:

and a compound having the formula:

R: R. O/

and a non-toxic acid addition salt thereof, wherein R is lower alkylhaving 1 to 6 carbon atoms,

R, is alkyl having 1 to 20 carbon atoms or cycloalkyllower-alkyl, thecycloalkyl part having 3 to 8 carbon atoms, and

X is an alkali or alkaline earth metal salt of the OH- group.

2. A compound of claim 1 having the formula:

CH; CH:

wherein R is alkyl of 1 to 20 carbon atoms or cycloalkyl-lower-alkyl,the cycloalkyl part having 3 to 8 carbon atoms.

3. A compound of claim 1 having the formula:

wherein R is lower alkyl having 1 to 6 carbon atoms.

4. A com-pound of claim 1 having the formula:

H; CH3 wherein R is methyl.

5. A compound of claim 1 having the formula:

wherein R is lower alkyl having 1 to 6 carbon atoms.

6. A compound of claim 1 having the formula:

wherein R is methyl.

7. A compound of claim 1 having the formula:

R2 CH3 12. The compound of claim 1 which is 2,2-dimethyl-7- n-penty1-4-(4-pyridyl) -2H-chromen-5-ol.

13. The compound of claim 1 which is 2,2,3-trimethyl- 7-n-pentyl-4-4-pyriclyl chroman-5-ol.

14. The compound of claim 1 which is 2,2-dimethyl-7-n-nonyl-4-(4-pyridyl)-2*H-chron1en-5-ol.

15. The compound of claim 1 which is 2,2-dimethyl-7-(2-octyl)-4-(4-pyridyl)-2H-chromen-5-ol.

16. The compound of claim 1 which is 2,2-dimethyl-7-(3-nonyl)-4-(4-pyridyl)-2H-chromen-5-ol.

17. The compound of claim 1 which is 2,2-diethyl-7-nheptyl-4- 4-pyridyl)-2H-chrornen-5-ol.

18. The compound of claim 1 which is 2,2-dimethyl-7- u-heptadecyll-(4-pyridyl) -2H-chromen-5-ol.

19. The compound of claim 1 which is 2,2-dimethyl-7-cycloheXyl-4-(4-pyridyl)-2H-chromen-5-ol. I

20. The compound of claim 1 which is 2,2-dimethyl-7- cyclopropyl-4-(4-pyridyl -2H-chromen-5-ol.

21. The compound of claim 1 which is 2,2-dimethyl-7- cyclobutyl-4-(4-pyridyl -2H-chromen-5-ol.

22. The compound of claim 1 which is 2,2-dimethyl-7-cycloheptyl-4-(4-pyridyl)-2H-chromen-5-ol.

23. The compound of claim 1 which is 2,2-dimethyl-7-cyclooctyl-4-(4-pyridyl)-2H-chromen-5-ol.

24. An alkali metal or alkaline earth metal salt of the compound ofclaim 1 which is:

-alkyl having 1 to 20 carbon atoms 25. The compound of claim 1 which is:

ONa

FOREIGN PATENTS 9/ 1968 Republic of South Africa ALAN L. ROTMAN, PrimaryExaminer US. Cl. X.R.

260295 F, 295 CA, 296 B; 424-263, 266

